Method for preparing α-arylpropionic acids

ABSTRACT

Process for preparing α-arylpropionic acids by catalytically asymmetrically hydrogenating α-arylpropenoic acids prepared from α-aryl ketones.

This is a continuation-in-part of U.S. patent application Ser. No.07/487,465, filed Mar. 2, 1990, which is a continuation-in-part of U.S.patent application Ser. No. 07/369,875, filed Jun. 22, 1989, now U.S.Pat. No. 4,994,607

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel synthetic route for preparingα-arylpropionic acids, e.g., 2-(6'-methoxy-2'-naphthyl)propionic acid(naproxen) and 2-(p-isobutylphenyl)propionic acid (ibuprofen), and tointermediates prepared and utilized in such synthetic route.

2. Prior Art

Naproxen is a nonsteroidal compound having anti-inflammatory,nonnarcotic analgesic and antipyretic activities. It belongs to a groupof compounds, generally classified as arylpropionic acids orarylalkanoic acids, which group includes naproxen, ibuprofen,ketoprofen, fenoprofen, suprofen, flurbiprofen, benoxaprofen, pirprofenand carprofen. Each of the compounds of this group are related in thatthey are propionic acid derivatives.

Many synthetic routes for producing arylpropionic acids and, inparticular, naproxen have been proposed. The first synthetic routesproduced a mixture of optical isomers or enantiomorphs. Thus, suchroutes required resolution of the mixture to obtain the more activeisomer, such as with cinchonidine or glucamine. These resolutionprocedures, however, require numerous recrystallizations and are,therefore, not commercially attractive.

More recently, attempts have been made for preparing thepharmaceutically useful optical isomer in excess of the physiologicallyinactive isomer so that the resolution procedure could be simplified.For example, U.S. Pat. No. 4,542,237 discloses a process for preparingα-arylpropionic acids and, in particular, a process for preparingnaproxen, which involves a noncatalytic rearrangement of a ketal orthioketal of 2-hydroxy-1-(6'-methoxy-2'-naphthyl)propan-1-one byactivating the α-hydroxy moiety with an esterifying agent to form thecorresponding alkyl aryl ketal or thioketal ester substrate. Concomitantor sequential hydrolysis of the ester produces the correspondingarylpropionic acid, 2-(6'-methoxy-2'naphthyl)propionic acid. See alsoPiccolo et al, J. Org. Chem. 52, 10-14 (1987), and references citedtherein. In the majority of cases, however, production of the desiredisomer in enantiomeric excess has been limited and numerousrecrystallizations are still required.

Asymmetric hydrogenation of arylpropenoic acids has been previouslyproposed as a method of further increasing the enantiomeric excess ofthe desired isomer. However, these procedures have had limited successin producing the desired optical isomer in enantiomeric excesssufficient to significantly simplify the resolution procedures. Forexample, Campolmi et al, U.S. Pat. No. 4,239,914 discloses catalyticasymmetric hydrogenation of 2-(6'-methoxy-2'-naphthyl)propenoic acidutilizing a chiral bidentate phosphine complex. Preferred compoundsinclude 1,2-ethanediylbis(o-methoxyphenyl)phenylphosphine (DIPAMP),[2,3-0-isopropylidene-2, 3-dihydroxy-1,4-bis(diphenylphosphine)butane](DIOP) andN,N'-bis-((+)-˜-methylbenzyl)-N,N'-bis-(diphenylphosphine)ethylenediamine(PNNP). The catalytic asymmetric hydrogenations are conducted with aDIOP catalyst at a temperature of 25° C. and at H₂ pressures of and 3.5atmospheres (˜15 p.s.i. and ˜52 p.s.i., respectively) and at 50° C. and3.5 atmospheres. Such a hydrogenation is also conducted with a PNNPcatalyst at 0° C. and 1 atm. Enantiomeric excess (e.e.) of the desiredproduct is reported to be about 70% or less.

Although Campolmi et al disclose that the hydrogenation can be conductedat temperatures of between 0° C. and 70° C. and at pressures of between1 and 50 atmospheres, it is reported in Asymmetric Catalysis, NATO ASISeries, Series E: Applied Sciences, pp. 24-26, B. Bosnich Editor,Martinus Nijhoff Publishers (1986) that in general catalytic asymmetrichydrogenations conducted at temperatures of less than about 25° C.and/or at pressures greater than about 15 psig H₂ result in decreasede.e.'s. See also Asymmetric Synthesis, Vol. 5--"Chiral Catalyst", pp.60-62, J. D. Morrison, Editor, Academic Press, Inc. (1985).

It has now been discovered, contrary to the above teachings, thatconducting asymmetric catalytic hydrogenations at temperatures belowabout 15° C. and, optionally, at H₂ pressures greater than about 5atmospheres, (˜75 psig) results in higher e.e.'s of the desired productsuch that resolution of the resulting optical isomer mixture issignificantly simplified. It has also been discovered that higher e.e.'scan be obtained by conducting such hydrogenations at temperatures of upto about 30° C. in the presence of an organic base or utilizing aspecific asymmetric hydrogenation catalyst.

For example, Noyori et al, J. Org. Chem. 52, 3174-76 (1987), discloseasymmetric hydrogenation of 2-(6'-methoxy-2'-naphthyl)propenoic acidwith a catalytic amount ofRu[(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl](CH₃ CO₂)₂ at about2000 psig H₂ and apparently, although not clearly, at 15°-30° C. toafford naproxen. However, it has now been discovered that utilizing thissame catalyst at temperatures below about 15° C. and, optionally, athigh H₂ pressures, significantly increases the enantiomeric excess ofthe desired isomer Furthermore, conducting the reaction in the presenceof an organic base, even at temperatures up to about 30° C.,significantly increases the enantiomeric excess of the desired isomer.

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed to a process forpreparing α-arylpropionic acids, and in particular for preparingnaproxen and ibuprofen, wherein high enantiomeric excess of the desiredoptical isomer is produced. The present invention resides in increasingthe enantiomeric excess of the desired product by conducting a catalyticasymmetric hydrogenation of the corresponding α-arylpropenoic acid attemperatures below or at about 30° C. under specific conditions. Thenovel process of this invention is particularly suited for preparing2-(6'-methoxy-2'-naphthyl)propionic acid and2-(p-isobutylphenyl)propionic acid. More particularly, the presentinvention is directed to an overall process for obtainingo-arylpropionic acids, particularly for obtaining naproxen andibuprofen, and to intermediates prepared and utilized in such process.This overall process is characterized by catalytic asymmetrichydrogenation of a dehydration product of an acid treatedelectrochemically carboxylated aryl ketone.

DETAILED DESCRIPTION OF THE INVENTION

As stated above, the present invention resides in the discovery thatα-arylpropenoic acids, such as 2-(6'-methoxy-2'-naphthyl)propenoic acid,can be converted to the corresponding α-arylpropionic acid in unexpectedenantiomeric excess utilizing an asymmetric hydrogenation catalyst atlow temperatures and, optionally, at high H₂ pressures. Examples ofα-arylpropenoic acids useful in the present invention include thoserepresented by the formula: ##STR1## wherein Ar is selected fromp-isobutylphenyl, 6-chlorocarbazyl-2, 3-phenoxyphenyl,2-isopropylindanyl-5, 2-fluoro-4-biphenyl and 6-methoxy-2-naphthyl. Apreferred α-arylpropenoic acid is 2-(6'-methoxy-2'-naphthyl)propenoicacid.

The α-arylpropenoic acids useful in the present invention can beprepared according to well-known procedures. A preferred procedureinvolves dehydration of an acid-treated electrochemically carboxylatedα-aryl ketone corresponding to said α-arylpropenoic acid.

The α-aryl ketones are prepared by methods well known in the art. Forexample, 2-acetyl-6-methoxynaphthalene can be prepared utilizing aFriedel Crafts acylation reaction with 2-methoxynaphthalene as startingmaterial.

A method for electrochemically carboxylating the α-aryl ketones, as wellas subsequent acid treatment, is described in detail in U.S. Pat. No.4,601,797 which is hereby incorporated by reference. In general, thereaction involves electrolyzing an aryl ketone at a cathode in thepresence of carbon dioxide and in an electrolysis medium to effectaddition of carbon dioxide to the aryl ketone. The electrochemicallycarboxylated aryl ketone is then treated with acid to produce thecorresponding 2-aryl-2-hydroxypropionic acid. This reaction is conductedat a pressure (CO₂) of from about 1 atm to about 30 atm, preferably fromabout 1 atm to about 10 atm, most preferably at about 5 atm. Thetemperature at which the reaction is conducted depends on the pressure(CO₂) that is utilized. At the preferred pressure of 5 atm, thepreferred temperature can range from about -5° to 40° C., preferably,40° C. At lower pressures the temperature can range from about -10° C.to about 10° C., preferably 0° C.

The 2-aryl-2-hydroxypropionic acids are then dehydrated by well-knowndehydration techniques to produce the corresponding α-arylpropenoicacid. One of such dehydration techniques involves utilization of asuspension of fused potassium acid sulfate in chlorobenzene at 130° C.for about 15 hours. Other solid catalysts such as KHSO₄ (other thanfused), polymer-bound sulfonic acids (resins) and the like, may also beutilized.

To increase the rate of reaction, the chlorobenzene may be replaced withdichlorobenzene and the reaction conducted at 150°-160° C. for two tothree hours. Other solvents such as organic solvents with boiling pointsabove about 100 C which will not react with the catalyst and substrateof the arylpropenoic acid may also be utilized. To achieve high yieldsof the desired product, small amounts, such as about 100 ppm to about10,000 ppm, based on the amount of 2-aryl-2-hydroxypropionic acid, of afree radical scavenger may be utilized. Exemplary free radicalscavengers include 2,6-di-t-butyl-4-methyl phenol, substituted andunsubstituted hydroquinones, dilauryl thiodipropionate and the like. Apreferred scavenger is 2,6-di-t-butyl-4-methyl phenol. Such free radicalscavengers can be used, alone or in combination.

The most preferred dehydration technique is novel and producesα-arylpropenoic acids in high yield and with very little or nodiscoloration. This technique involves utilization of a solvent systemwhich includes a low molecular weight carboxylic acid, such as, forexample, acetic acid or propionic acid. The low molecular weightcarboxylic acid, while serving as a solvent, also serves as thedehydration catalyst The solvent system can include other solvents aswell, such as, for example, xylene, toluene, benzene and the like

The α-arylpropenoic acids are then asymmetrically hydrogenated utilizingan asymmetric hydrogenation catalyst at low temperatures. Thehydrogenation reaction is conducted at a temperature below about 15° C.,preferably below about 10° C. such as below or at about 5° C. The lowerlimit on the temperature at which the reaction is conducted is notcritical as the temperature can be as low as -15° C. with excellentresults in terms of high enantiomeric excess of the desired product.

Optionally, the hydrogenation reaction can be conducted at highpressure. Preferably, the hydrogenation reaction is conducted at H*pressure above about 65 psig such as above about 75 psig, for example,at 1000 psig H*. The upper limit on the hydrogen pressure is notcritical, however, such upper limit will depend on the capability of theequipment being utilized.

Examples of suitable asymmetric hydrogenation catalysts include rhodium(Rh) and ruthenium (Ru) complexes of chiral phosphine compounds. Suchcatalysts are described in Asymmetric Synthesis, Volume 5--"ChiralCatalyst" (1985), and Asymmetric Catalysis, NATO ASI Series, Series E.(1986), both of which are referenced above. More particularly,DIPAMP-type catalysts are disclosed in U.S. Pat. No. 4,142,992 to W. S.Knowles et al. Preparation of the bis phosphine compounds is disclosedin U.S. Pat. No. 4,008,281, also to W S. Knowles, et al. Opticallyactive binaphthyl compounds are more particularly disclosed in Noyori etal, J. Am. Chem. Soc., 109, 5856-58 (1987) and J. Org. Chem. 52, 3174-76(1987), as Well as optically active bisphosphine catalysts (DIOP-typecatalysts) more particularly disclosed in U.S. Pat. No. 4,142,992.

Thus, a suitable asymmetric hydrogenation catalyst is one selected fromthe group consisting of a) a rhodium or ruthenium complex havingoptically active bis phosphine compounds of the formula ##STR2## whereinA and B each independently represent substituted and unsubstituted alkylradicals having from 1 to about 12 carbon atoms, substituted andunsubstituted cycloalkyl radicals having from about 4 to about 7 carbonatoms, and substituted and unsubstituted aryl radicals; provided thatsuch substituents provide no significant interference with the stericrequirements around the phosphorus atom, and A and B are different, b)optically active bisphosphine binaphthyl compounds of the formulaRu(BINAP)(OCOR)₂ and Ru_(x) H_(y) Cl_(z) (BINAP)₂ (S)_(p) wherein BINAPrepresents a tertiary phosphine of the formula: ##STR3## in which Rrepresents substituted and unsubstituted alkyl radicals having from 1 toabout 6 carbon atoms, substituted and unsubstituted halogenated alkylradicals having from 1 to about 6 carbon atoms, substituted andunsubstituted aryl radicals, and substituted and unsubstituted aralkylradicals; R¹ represents hydrogen, substituted and unsubstituted alkylradicals having 1 to about 6 carbon atoms and substituted andunsubstituted aryl, aralkyl and alkaryl radicals, S is a tertiary amineand when y=o, x=2, z=4 and p=0 or 1, when y=1, x=1, z=1 and p=0; c) Rhor Ru catalysts containing chiral phosphines represented by the formula:##STR4## wherein R² represents substituted and unsubstituted alkylradicals having from 1 to about 12 carbon atoms, substituted andunsubstituted cycloalkyl radicals having from about 4 to about 7 carbonatoms and substituted and unsubstituted aryl, aralkyl and alkarylradicals; and d) phosphine complexes represented by the formulas:

Ru[L](OCOR³)₂ and Ru_(x) H_(y) Cl_(z) [L]₂ (S)_(p) wherein L representsa phosphine of the formula: ##STR5## wherein R³ represents substitutedand unsubstituted alkyl radicals having from 1 to about 6 carbon atoms,substituted and unsubstituted halogenated alkyl radicals having from 1to about 6 carbon atoms, substituted and unsubstituted aryl radicals andsubstituted and unsubstituted aralkyl and alkaryl radicals; R⁴represents H, substituted and unsubstituted alkyl radicals having 1 toabout 6 carbon atoms and substituted and unsubstituted alkoxy radicalshaving I to about 6 carbon atoms; R⁵ represents alkyl radicals havingfrom 1 to about 6 carbon atoms and substituted and unsubstituted arylradicals, S is a tertiary amine and when y=0, x=2, z=4 and p=0 or 1 andwhen y=1, x=1, z=1 and p=0. Many other asymmetric hydrogenationcatalysts are well-known in the art and it is contemplated that suchcatalysts can also be utilized in the present invention with similarlyimproved results. A preferred catalyst is an optically active rutheniumbinaphthyl compound, preferably the chloro derivative rather than theacetate Exemplary catalysts include [RuCl₂ (BINAP)]₂ (NEt₃),RuHCl(BINAP)₂, Ru(BINAP)(BF₄)₂. Additional exemplary binaphthylcatalysts include those prepared by reacting a ruthenium chloridecomplex with a binaphthyl ligand. Further exemplary catalysts includethose wherein the chloride ligand is replaced with BF₄₋, ClO₄₋, PF₆₋ orBPh₄₋, and/or those wherein the binaphthyl ligand is replaced with abiaryl ligand. These types of catalysts are disclosed in U.S. Pat. No.4,766,225 as not being satisfactory in terms of the optical yieldattained. However, it has now been discovered that utilization of suchcatalysts for catalytic hydrogenation of α-arylpropenoic acids producesthe corresponding α-arylpropionic acids in extremely high enantiomericexcess.

The catalytic hydrogenations utilizing such catalysts are conductedaccording to known conventional techniques in a homogeneous system whichincludes the catalyst, an organic solvent and, optionally, a base,preferably an organic base such as a nitrogenous base, for example,triethylamine, tributylamine and other organic amines, preferably othertertiary amines. Examples of suitable inorganic bases include sodiumhydroxide and potassium hydroxide. The use of a base, particularly inconjunction with a ruthenium catalyst, serves to increase theenantiomeric excess of the α-arylpropionic acid. It has been found thatwhen a base is employed with a ruthenium catalyst satisfactory resultswith respect to enantiomeric excess are obtained when temperatures ashigh as about 30° C. are employed However, in essentially all cases itis preferred to use below about 15° C. temperatures.

The catalyst/substrate molar ratio may vary between about 1:20 and about1:20,000 preferably about 1:100 to about 1:10,000. A preferredcatalyst/substrate molar ratio is about 1:10,000. Thesubstrate/nitrogenous base molar ratio may vary between about 100:1 andabout 1:5, preferably about 10:1 to about 1:1. The substrate/solventratio may vary between about 1:10,000 and about 1:1 by weight,preferably about 1:100 and about 1:3. These catalysts can be utilized inthe form of complexes of a bis olefin, an arene or coordinated solvents.

Ruthenium complex catalysts of the formula:

    [Ru(BINAP)XY].sub.n

wherein X and Y are nonchelating anionic ligands, for example, H, I, Br,Cl or F or noncoordinating or weakly coordinating anions, for example,BF₄₋, ClO₄₋, PF₆₋ or BPh₄₋ with X and Y being either the same ordifferent, are especially effective when employed with a base such as alower trialkylamine or an alkali metal hydroxide. Even when no base isemployed and the temperature does not exceed 30° C. satisfactory resultsare obtained with this particularly preferred catalyst.

A preferred synthesis for naproxen involves the following reactionsequence, the subject asymmetric catalytic hydrogenation of thisinvention being conducted as a last step: ##STR6##

In this preferred synthesis, the first step is a typical Williamsonether synthesis involving reaction of 2-hydroxynaphthalene(1) with amethylating agent such as methyl sulfate to produce2-methoxynaphthalene(2). Alternatively, 2-methoxynaphthalene isavailable commercially from Sigma-Aldrich.

The second step involves a Friedel Crafts acylation reaction of2-methoxynaphthalene(2) to produce the corresponding2-acetyl-6-methoxynaphthalene(3). Friedel Crafts acylation ofnaphthalene derivatives is a well known procedure as described in Jap.SHO-59-51234, which is incorporated herein by reference.

The third step involves electrochemical carboxylation of the acetylmoiety of 2-acetyl-6-methoxynaphthalene(3) followed by acid treatment toafford 2-(6'-methoxy-2'-naphthyl)-2-hydroxypropionic acid (4). As statedabove, electrochemical carboxylation of aryl ketones followed by acidtreatment is fully described in U.S. Pat. No. 4,601,797 to J. H.Wagenknecht, which is incorporated herein by reference.

Dehydration of (4) to produce 2-(6'-methoxy-2'-naphthyl)propenoic acid(5) is carried out in the fourth step utilizing propionic acid as bothcatalyst and solvent as previously described. Other acid catalysts, aspreviously described, may also be utilized.

Thus, in one aspect, the present invention is directed to a method ofproducing α-arylpropionic acids in high enantiomeric excess utilizing anasymmetric hydrogenation catalyst at temperatures below about 15° C.and, optionally, at pressures greater than about 75 psig H₂.

In another aspect, the present invention is directed to asymmetriccatalytic hydrogenation of the dehydration product of an acid treatedelectrochemically carboxylated aryl ketone.

In another aspect, the present invention is directed to a method ofpreparing naproxen by catalytically asymmetrically hydrogenating thedehydration product of an acid-treated electrochemically carboxylated2-acetyl-6-methoxynaphthalene.

In yet another aspect, the present invention is directed to catalyticasymmetric hydrogenation of 2-(6'-methoxy-2'-naphthyl)propenoic acid attemperatures below about 15° C. and, optionally, at pressures aboveabout 75 psig H₂.

Contemplated equivalents of the catalysts and compounds set forth above,as well as the intermediates, are compounds otherwise correspondingthereto and having the same general properties with simple variations ofthe substituents. In addition, where a substituent is designated as, orcan be, a hydrogen, the exact chemical nature of a substituent which isother than hydrogen at that position is not critical so long as it doesnot adversely affect the overall synthesis procedure.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

Optical yields were determined by either a standard optical rotationprocedure or by chiral gas chromatography of the corresponding menthol(commercially available (+)-isomer obtained from Sigma-Aldrich) esterderivatives utilizing a CHIRASIL-VAL-L column obtained from Chrompack.

EXAMPLE 1

This example illustrates the effect of reaction temperature on theenantiomeric excess of the desired product obtained by catalyticasymmetric hydrogenation according to the teachings of the presentinvention.

A glass-lined stainless steel reactor was charged with 0.02 g ofα-(6'-methoxy-2'-naphthyl) propenoic acid (prepared as in Example 3),0.02 g triethylamine, 0.0003 g [Rh(COD)(DIPAMP)]BF₄ (prepared accordingto the procedure set forth in U.S. Pat. No. 4,142,992), and 4 g ofmethanol. The solution was stirred well with a magnetic stirrer atvarious temperatures and H₂ pressures for 16 hours. Results are reportedin Table 1.

It should be noted that with this DIPAMP catalyst a decrease intemperature results in a significant increase in e.e. of the desiredproduct. For example, comparing runs A and B, a decrease in temperaturefrom 23° C. to 5° C. results in a 7% increase in e.e. Reducing thetemperature another 10° C. to -5° C., as in run C, results in an 18.8%total increase in e.e. In addition, comparing runs a, d and e, anincrease in pressure from 80 to 700 psig H* results in a 19% increase ine.e and an additional increase of 100 psig to 800 results in an overallincrease in e.e. of 26%.

                  TABLE 1                                                         ______________________________________                                                                   Enantiomeric Excess                                                           of α-(6'-methoxy-2'-                                Temp..sup.1                                                                              H.sub.2 Press.                                                                         naphthyl)propionic                                 Run    (°C.)                                                                             (psig)   acid.sup.1                                         ______________________________________                                        a.     23         700      69                                                 b.      5         700      74                                                 c.     -5         700      82                                                 d.     23         800      73                                                 e.     23          80      58                                                 ______________________________________                                         .sup.1 Product recovered as the triethylammonium salt.                   

EXAMPLE 2

This Example illustrates the effect of temperature with differentasymmetric hydrogenation catalysts. A 50 ml stainless steel autoclavewith a glass liner and a magnetic stirring bar was charged withα-(6'-methoxy-2'-naphthyl)propenoic acid (prepared as in Example 3) inthe amount indicated in Table 2, one equivalent of triethylamine, 3 gdegassed methanol (solvent), and a catalyst as identified in Table 2 inthe amount indicated. The solution was then stirred at the temperatureand under the H₂ pressure indicated in Table 2 for the period indicated.

Comparing runs a and c, a combination of decreased temperature andincreased pressure results in an 18% increase in e.e. with the DIOPcatalyst. Similarly, comparing runs d and g, a combination of decreasedtemperature and increased pressure results in a 35% increase in e.e withthe BINAP catalyst. In addition, a decrease in temperature without anincrease in pressure results, as shown by comparing runs e and g andruns d and h, in an increase in e.e. ranging from 10% at higherpressures, i.e., 1000 psig, to 23% at nominal pressures of 200 psig.

                                      TABLE 2                                     __________________________________________________________________________       mg Precursor          mg Cat.                                                                             Temp                                                                              Pressure                                                                           Rxn Time                                                                            e.e.                            Run                                                                              (mmol) Catalyst       (mmol)                                                                              (°C.)                                                                      (psig H.sub.2)                                                                     (hrs) (%)                             __________________________________________________________________________    a. 50 (0.22)                                                                            [Rh(COD)((-)-DIOP)]ClO.sub.4.sup.1                                                           6.2 (0.0077)                                                                        25   45  16    73.1                            b. "        "            "     25  1000 16    79.2                            c. "        "            "     -5  1000 16    86.3                            d. 20 (0.088)                                                                           Ru(R-BINAP)(OAc).sub.2.sup.2                                                                 1.3 (0.0015)                                                                        25   200 16    66.5                            e. "        "            "     25  1000 65    81.5                            f. "        "            "     -6  2000 14    88.0                            g. "        "            "     -6  1000 19    89.7                            h. "        "            "     -6   200 16    89.3                            __________________________________________________________________________     .sup.1 Prepared according to the procedure set forth in J. Amer. Chem.        Soc., 2397-2407 (1971) utilizing (-)-DIOP as the phosphine ligand and         AgClO* as an anion source.                                                    .sup.2 Prepared according to the procedure set forth in J. Org. Chem., 52     3174-76 (1987)                                                           

EXAMPLE 3

This example illustrates one embodiment for the synthesis of naproxenaccording to the teachings of the present invention.

Synthesis of 2-acetyl-6-methoxynaphthalene

A 2-liter, 3-neck flask equipped with a mechanical stirrer was chargedwith 700 mL nitrobenzene The solvent was cooled to ˜10° C. with an icebath, and into this was added 54.4 g aluminum trichloride (0.408 o mole)while the mechanical stirring was continued. After the AlCl₃ wasdissolved, 56.5 g 2-methoxynaphthalene (0.36 mole) was added to thesolution. The mixture was cooled to 5°-8° C. While the temperature wasmaintained at about 8° C., 33 g of acetyl chloride (0.42 mole) was addedslowly to the mixture (in a period of about one hour). After all theacetyl chloride was added, the stirring at 8° C. was continued for 3hours.

The stirring was stopped and the flask was placed in a constanttemperature bath. The reaction mixture was allowed to stand at 40°±2° C.for 20 hours. The content of the flask was then poured into a largebeaker which contained one liter of ice water and 100 mL concentratedHCl. The cold mixture was stirred with a magnetic stirrer for 30 minutesand then allowed to stand for 20 minutes for phase separation. (Foreasier phase separation, usually ˜100 mL chloroform was added to themixtures.)

The organic layer was collected and washed with dilute sodiumbicarbonate solution and then ion-exchanged water (2-3 times, untilneutral).

The organic solvents were stripped in a rotary evaporator and theresidue was distilled in a Kugelrohr apparatus (0.5 mm Hg, 100°-120°C.). The crude yellow product (68 g) collected in the receiver wasrecrystallized in 100 mL hot methanol by cooling to ˜5° overnight. Thewhite crystals were filtered and washed with ˜50 mL cold methanol twice.After drying in vacuo for 24 hours, 56 g pure2-acetyl-6-methoxynathphalene (79% theoretical yield) was obtained. Themethanol washing and the mother liquor were combined and evaporated todryness. ¹ H NMR of the residue showed ˜4 g2-acetyl-6-methoxynaphthalene and ˜5 g 1-acetyl-2methoxynaphthalene init. These can be separated by further crystallization.

Synthesis of Hydroxynaproxen (2-(6'-Methoxy-2'-Naphthyl)Lactic acid)

A one-liter reaction vessel was fitted with a 100 cm² lead cathode and a100 cm² aluminum anode and a mechanical stirrer. Into this reactor wereadded 10 g of 2-acetyl-6-methoxynaphthalene, 15 g of tetrabutylammoniumbromide (electrolyte), and 500 mL dry DMF. The mixture was stirred tomake a homogeneous solution and then cooled to ˜0° C. while dry CO₂ gaswas bubbling through. After 30 minutes of CO₂ bubbling (to saturate thesolution with CO₂), the constant current power supply was turned on and0.6 A current (11 V) was allowed to pass the solution while the stirringand CO₂ bubbling was continued. The electrolysis was continued for 5hours. After the shutoff of electricity and CO₂, the DMF solution wascollected in a round-bottom flask. The solvent was stripped in a rotavacand the residue was shaken well with ˜100 mL water for 3 hours. Thesolid material was filtered off and then stirred in 100 o mL water and50 mL conc. HCl for 3 hours. The white solid was filtered and washedwith 4 portions of ˜30 mL water. The product was dried in vacuo for 3days. Analysis of this dry powder indicated 8.8 gα-(6'-methoxy-2'-naphthyl)lactic acid product and 1.8 g2-acetyl-6-methoxynaphthalene (starting material) in the solid material.The starting material was removed from the product by repeated washingwith toluene.

Synthesis of 2-(6'-methoxy-2'-naphthyl)propenoic acid

A 250 mL round bottom flask was charged with 7.5 gα-(6'-methoxy-2'-naphthyl)lactic acid, 12.5 g fused potassium bisulfate,0.007 g dilauryl thiodipropionate, 0.02 g 2,6-di-t-butyl-4-methylphenol,and 80 mL 1,2-dichlorobenzene (solvent). The mixture was stirred well at160° C. for 3 hours and then filtered. The solid was washed with 100 mLhot methylene chloride and filtered. The filtrates were combined andevaporated to dryness in a rotavac. 95% yield of2-(6'-methoxy-2'-naphthyl) propenoic acid was obtained.

Hydrogenation of 2-(6'-methoxy-2'-naphthyl)propenoic acid

A 100 mL stainless steel autoclave was charged with 5 g2-(6'-methoxy-2'-naphthyl)propenoic acid, 2.2 g triethylamine, 0.04 g[Ru₂ Cl₄ (S-BINAP)₂ ]NEt₃, and 80 mL o methanol under nitrogenatmosphere. The mixture was stirred well under 800 psig H₂ at -2° C. for16 hours. Analysis of the product solution indicated quantitativechemical yield of Naproxen with 96% e.e. It is contemplated that theactual time to completion may be shorter.

EXAMPLE 4

This example illustrates the extremely high e.e.s obtained utilizing thechloro-Ru-BINAP catalyst complexes and illustrates the best mode forconducting the asymmetric hydrogenation of α-arylpropenoic acids withsuch catalyst. The first two catalysts listed in Table 3 were preparedaccording to the procedure set forth in EP 0272787 A2 and all catalystswere utilized with molar ratios of substrate/catalyst/solvent/aminesimilar to those of Example 3. Thus, a ruthenium chloride derivative isreacted with cycloocta-1,5-diene (COD) in an ethanol solution and onemole of the resulting complex is reacted with 1.2 moles of the desiredBINAP derivative under heating and in a solvent such as toluene orethanol in the presence of 4 moles of a tertiary amine such astriethylamine. All hydrogenations were conducted in the presence oftriethylamine (1 m/m) except as noted.

                  TABLE 3                                                         ______________________________________                                                       Press.           Reaction                                      Catalyst       (psig H.sub.2)                                                                         T(°C.)                                                                         t (hrs)                                                                              % e.e.                                 ______________________________________                                        RuHCl(BINAP).sub.2                                                                           500      -6      14     97.7                                   [Ru.sub.2 Cl.sub.4 (BINAP).sub.2 ](NEt.sub.3)                                                500      -7      91     98.1                                   Ru(Benzene)Cl.sub.2 +BINAP.sup.1                                                             500      -6      14     97.2                                   Ru(DMSO).sub.4 Cl.sub.2 +BINAP.sup.1                                                         500      -4      62     97.5                                   Ru(COD)Cl.sub.2 +BINAP+                                                                      100      -5      16     94.4                                   NEt.sub.3.sup.2                                                               Ru(COD)Cl.sub.2 +BINAP+                                                                      1000     -5      16     97.1                                   NEt.sub.3.sup.2                                                               Ru(COD)Cl.sub.2 +BINAP+                                                                      1000     -5      16     92.2                                   NEt.sub.3.sup.2,3                                                             Ru(COD)Cl.sub.2 +BINAP+                                                                      1000     25      16     91.7                                   NEt.sub.3.sup.2,3                                                             ______________________________________                                         .sup.1 Refluxed in toluene for 16-20 hrs. and utilized in situ.               .sup.2 Stirred in toluene @ 120° C. for 10 hrs. solvent evaporated     and residue washed with MeOH and then dried in vacuo.                         .sup.3 3Hydrogenation conducted in absence of triethylamine.             

EXAMPLE 5

This example illustrates the temperature and pressure effects on thee.e. utilizing [Ru₂ Cl₄ (BINAP)₂ ](NEt₃) (under conditions similar tothose of Example 4) in the presence of triethylamine to hydrogenate2-(6'-methoxy-2'-naphthyl)propenoic acid, prepared as in Example 3.Results are reported in Table 4.

                  TABLE 4                                                         ______________________________________                                        Pressure (psig H.sub.2)                                                       e.e.         T (°C.)                                                                          Reaction t (hr.)                                                                          %                                          ______________________________________                                        100          -7        91          95.3                                       200          "         "           96.7                                       500          "         "           98.1                                       2000         "         "           98.5                                       100          11        15          85.0                                       200          "         "           89.8                                       500          "         "           95.2                                       1000         "         "           95.4                                       100          25        16          70.6                                       200          "         "           82.6                                       500          "         "           90.1                                       1000         "         "           93.3                                       ______________________________________                                    

EXAMPLE 6

This example illustrates the temperature and pressure effects on e.e.for naproxen utilizing Ru(BINAP)(OAc)₂ in the presence of triethylamineas catalyst (prepared according to the procedure of Noyori et al) underconditions similar to those of Example 5. Results are reported in Table5.

                  TABLE 5                                                         ______________________________________                                        Pressure (psig H.sub.2)                                                                    T (°C.)                                                                          Reaction t (hr.)                                                                          % e.e.                                     ______________________________________                                        a.       200     -6        16        89.3                                     b.      1000     -6        19        89.7                                     c.      2000     -6        14        88.0                                     d.       200     25        16        66.5                                     e.sup.1.                                                                              1000     25        16        83.9                                     f.      1000     25        65        81.5                                     g.      1800     28        14        84.7                                     ______________________________________                                         .sup.1 Conducted in the absence of triethylamine.                        

EXAMPLE 7

This example illustrates the effectiveness of the use of a base in theasymmetric hydrogenation of α-arylpropenic acids. The results are givenin Table 6.

                                      TABLE 6                                     __________________________________________________________________________                            Reaction                                                             Pressure Time        %                                         Catalyst       (psig H.sub.2)                                                                     T (°C.)                                                                    (hours)                                                                            Base   Conv.                                                                             % e.e.                                __________________________________________________________________________    [Ru(S-BINAP)I.sub.2 ].sub.n                                                                  1000 -3  16   Triethylamine                                                                        100 96                                    [Ru(S-BINAP)Br.sub.2 ].sub.n                                                                 "    "   "    "      "   "                                     [Ru(S-BINAP)Cl.sub.2 ].sub.n                                                                 "    "   "    "      "   "                                     [Ru(S-BINAP)(BF.sub.4).sub.2 ].sub.n                                                         "    "   "    "      "   98                                    [Ru(S-BINAP)F.sub.2 ].sub.n                                                                  "     0  "    "       95 96                                    [Ru(S-BINAP)F.sub.2 ].sub.n                                                                  "    "   "    None   100 93                                    [RuCl.sub.2 (S-BINAP)].sub.2 1.NEt.sub.3                                                     "    -5  "    Triethylamine                                                                        "   97.1                                  [RuCl.sub.2 (S-BINAP)].sub.2.NEt.sub.3                                                       "    "   "    None   "   92.2                                  [Ru(S-BINAP)(benzene)Cl]Cl                                                                   "     0  14   "       37 86.4                                  [Ru(S-BINAP)(benzene)Cl]Cl                                                                   "    "   "    Triethylamine                                                                         61 98.4                                  ([Ru(S-BINAP)][BF.sub.4 ].sub.2).sub.n                                                       "    -3  64   None    65 87                                    ([Ru(S-BINAP)][BF.sub.4 ].sub.2).sub.n                                                       "    "   "    Triethylamine                                                                         75 95                                    __________________________________________________________________________

EXAMPLE 8

This example shows the hydrogenation of 2-(p-isobutylphenyl)propenoicacid to produce 2-(pisobutylphenyl)propionic acid using the general shydrogenation procedure of Example 3. The catalyst was [RuCl₂(S-BINAP)]₂ NEt₃ and the base was triethylamine. In each run the yieldof 2-(p-isobutylphenyl)propionic acid (as the triethylammonium salt) was100%. The results are reported in Table 7.

                  TABLE 7                                                         ______________________________________                                        Pressure (psig H.sub.2)                                                                    T (°C.)                                                                          Reaction t (hr.)                                                                          % e.e.                                     ______________________________________                                        a.       100     -5        24        88                                       b.       100     25        24        71                                       c.      1000     -5        24        96                                       d.      1000     25        24        87                                       ______________________________________                                    

EXAMPLE 9

This example illustrates the preferred method for catalyticallydehydrating hydroxynaproxen and compares such preferred method to awell-known method.

A. Preferred Method 1

A 100 mL round-bottomed flask magnetic stirring bar was charged with 0.5g of hydroxynaproxen and 10 mL of acetic acid. The mixture was refluxedwith magnetic stirring for 4 hors. Evaporation of the acetic acid gave0.44 g of white dehydronaproxen in 95% yield.

Preferred Method 2

A 100 mL round-bottom flask with a magnetic stirring bar was chargedwith one gram of hydroxynaproxen and 10 mL propionic acid. The mixturewas magnetically stirred at reflux temperature for two hours.Evaporation of the solvent in vacuo gave 0.88 g dehydronaproxen (95%yield) with little discoloration.

B. Known Method

A 100 mL round-bottomed flask with a s magnetic stirring bar was chargedwith 0.5 g hydroxynaproxen, 2.5 g fused potassium acid sulfate(catalyst), and 10 mL ortho-dichlorobenzene (solvent). The mixture wasrefluxed with magnetic stirring for four hours. The resulting solutionwas deep red. The mixture was filtered while still hot with a hotfiltering funnel. The filtrate was evaporated to dryness. Thedehydronaproxen product (0.44 g, 95% yield) was of undesirable deep redcolor. To clear up this color, decoloration with activated carbon andrepeated crystallation were required. A substantial product loss wasobserved during this clean-up process.

EXAMPLE 10 Synthesis of Hydroxynaproxen(2-[6'-Methoxy-2'-Naphthyl]Lactic Acid) Via Electrocarboxylation

A reaction vessel was fitted with a 400 cm² lead cathode and asimilar-sized aluminum anode. A reaction solution was prepared bydissolving 36 g 2-acetyl-6-methoxynaphthalene and 60 gtetrabutylammonium bromide in 1.8 liter N,N-dimethylformamide (DMF). Thesolution was continuously circulated through the reaction vessel at arate of about 4 gallons per minute by using a circulation pump. Thereaction system was pressurized with carbon dioxide and about 40 psigCO₂ pressure was maintained throughout the reaction. A direct current ofsix ampere was applied to the system and the reaction was carried out at40°-42° C. for 1.5 hours. Analysis of the product after hydrolysisindicated 80% conversion of the 2-acetyl-6-methoxynaphthalene with 95%selectivity for the desired hydroxynaproxen.

EXAMPLE 11 Catalytic Dehydration of2-(4-Isobutylphenyl)-2-Hyroxypropionic Acid

A 250 mL round-bottomed flask was charged with 0.5 g2-(4-isobutylphenyl)-2-hydroxypropionic acid, 5 g fused potassiumbisulfate, 0.001 g 1,6-di-t-butyl-4-methylphenol, and 100 mLchlorobenzene. The mixture was stirred with a magnetic stirring bar at130° C. for two days. ¹ H NMR analysis of the resulting productindicated 100% conversion of the starting material to the desired2-(4-isobutylphenyl)propenoic acid.

It is contemplated that utilization of other asymmetric hydrogenationcatalysts such as complexes of other optically active bis phosphinecompounds, biaryl compounds and binaphthyl compounds will producesimilar results when utilized according to the teachings of the presentinvention.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. Process for preparing naproxen comprising:a)electrochemically carboxylating 2-acetyl-6-methoxy-naphthalene to afford2-(6'-methoxy-2'-naphthyl)-2-hydroxypropionic acid; b) dehydrating the2-(6'-methoxy-2'-naphthyl)-2hydroxypropionic acid of step a) to afford2-(6'-methoxy-2'-naphthyl)propenoic acid; and c) catalyticallyasymmetrically hydrogenating the 2-(6'-methoxy-2'-naphthyl) propenoicacid of step b).
 2. Process of claim 1 wherein Step b) is conducted in alow molecular weight carboxylic acid selected from acetic acid andpropionic acid.
 3. Process of claim 1 wherein Step c) is conductedutilizing a ruthenium asymmetric hydrogenation catalyst at a temperatureof less than about 30° C.
 4. Process of claim 3 wherein the catalyst isrepresented by the formula:

    [Ru(BINAP)XY].sub.n

wherein X and Y represent a nonchelating anionic ligand or anoncoordinating anion.
 5. Process of claim 3 wherein the temperature isless than about 15° C.
 6. Process of claim 1 wherein said2-acetyl-6-methoxynaphthalene is obtained by a Friedel Crafts acylationof 2-methoxynaphthalene.
 7. Process of claim 6 wherein said2-methoxynaphthalene is obtained by Williamson ether synthesis utilizinga methylating agent and 2-hydroxynaphthalene.
 8. A process for preparingan α-arylpropionic acid comprising:(a) electrochemically carboxylatingan α-arylketone to produce an 2-aryl-2-hydroxypropionic acid, (b)dehydrating said 2-aryl-2-hydroxypropionic acid to produce anα-arylpropenoic acid, and (c) catalytically asymmetrically hydrogenatingsaid α-arylpropenoic acid to produce said α-arylpropionic acid.
 9. Theprocess of claim 8 wherein the dehydration of said2-aryl-2-hydroxypropionic acid is conducted in a low molecular weightcarboxylic acid selected from the group consisting of acetic acid andpropionic acid.
 10. The process of claim 8 wherein the catalyticasymmetric hydrogenation of said α-arylpropenoic acid is conductedutilizing a ruthenium asymmetric hydrogenation catalyst selected fromthe group consisting of optically active bisphosphine binaphthylcompounds of the formula Ru(BINAP)(OCOR)₂, Ru_(x) H_(y) Cl_(z) (BINAP)₂(S)_(p) and [Ru(BINAP)XY]_(n), wherein BINAP represents a tertiaryphosphine of the formula: ##STR7## R represents substituted andunsubstituted alkyl radicals having 1 to about 6 carbon atoms,substituted and unsubstituted halogenated alkyl radicals having 1 toabout 6 carbon atoms, and substituted or unsubstituted aryl, arylkyl andarlkaryl radicals, R' represents hydrogen, substituted or unsubstitutedalkyl radicals having 1 to about 6 carbon atoms, and substituted orunsubstituted aryl, aralkyl and alkaryl radicals, S is a tertiary amine,X and Y independently represent a nonchelating anionic ligand or anoncoordinating anion, y is 0 or 1, and when y=0, x=2, z=4 and p=0 or 1,and when y=1, x=1, y=1 and p=0, and wherein said catalytic asymmetrichydrogenation is conducted at a temperature of less than about 30° C.11. The process of claim 10 wherein said catalytic asymmetrichydrogenation is conducted in the presence of a base.
 12. The process ofclaim 10 wherein said catalyst is represented by the formula:[Ru(BINAP)XY]_(n) wherein X and Y independently represent a nonchelatinganionic ligand or a noncoordinating anion.
 13. The process of claim 10wherein said temperature is less than about 15° C.
 14. The process ofclaim 8 wherein said α-arylpropionic acid is selected from the groupconsisting of naproxen, ibuprofen, ketoprofen, pirprofen, fenoprofen,suprofen, flurbiprofen, benoxaprofen and carprofen.
 15. The process ofclaim 14 wherein said α-arylpropionic acid is selected from the groupconsisting of naproxen and ibuprofen.